Project Summary/Abstract Hearing loss is a growing epidemic with estimates that by 2050 over 900 million people will have difficulty hearing. Hearing loss negatively impacts almost every aspect of the human experience. In addition, it is correlated to promoting cognitive decline and increased risk of dementia. The most common cause of hearing loss is sensorineural as hair cells and spiral ganglion neurons, the two cell types essential for transducing auditory information, are lost. While our understanding of the genes and the signaling cascades that regulate hair cells and spiral ganglion neurons continues to grow at an explosive pace, the ability to translate this knowledge into effective treatments for curing hearing loss lags far behind. Currently, there is no known biological treatment for hearing restoration. However, viral vector-based gene therapy strategies have shown tremendous potential. Currently, our understanding of their safety, efficacy, and long-term stable transduction in the adult cochlea is still in the early stages. The goal of this application is to bridge this gap by developing a recombinant viral vector for gene therapy approaches for the treatment of hearing loss. Therefore, our objective will be to generate and characterize the safety, efficacy, and cell type-specific transduction patterns of a helper-dependent adenovirus vector in a normal functioning cochlea and a deafened cochlea. Our knowledge gained will be of tremendous value for the development of effective gene therapy approaches in the inner ear.